Alzheimer disease (AD) pathology is characterized by beta-amyloid (A) plaques and tau-containing neurofibrillary tangles. Recent evidence suggests that soluble forms of both A and tau can influence cognition and A has been shown to modulate tau pathology. However, the A species that mediates these effects remains largely unresolved. The Arctic A mutation (E22G) has recently been shown to enhance soluble A protofibril formation and cause early-onset familial AD, providing strong genetic evidence that A aggregation state is critical to the development of AD. In this proposal, we will utilize the Arctic mutation to test the hypothesis that soluble A assemblies induce tau pathology and cognitive dysfunction. To facilitate my investigation and greatly enhance my career development, I will receive mentorship from Dr. Frank LaFerla in the design, generation and analysis of transgenic AD models. In addition, Dr. James McGaugh and Dr. Charles Glabe will provide me with training in behavioral analyses and oligomeric protein biochemistry respectively. In Aim 1, we will utilize the Arctic A mutation to develop novel transgenic models of AD with age-dependent and progressive neuropathology to test the hypothesis that soluble A assemblies promote tau pathology from wild type hTau. We anticipate that this model will develop A and tau pathologies without the use of mutant tau, thereby more closely representing the etiology of AD. In Aim 2, we will assess cognitive phenotype and correlations with A and tau pathology. Soluble Arctic A inhibits hippocampal LTP 100-fold more potently than wild-type A. Therefore, we hypothesize that the Arctic mutation will rapidly produce cognitive dysfunction via enhancing the generation of soluble A assemblies and modulating the development of tau pathology. Under the guidance of Dr. James McGaugh, I will test this hypothesis by performing a cross-sectional analysis of cognitive function in our novel transgenic models and determine whether cognitive deficits correlate with pathological progression. In Aim 3 we will test the hypothesis that soluble A assemblies induce tau pathology and mediate cognitive decline. In this aim, Dr. Charles Glabe will provide guidance on oligomeric protein biochemistry and his conformational-dependent antibodies will be utilized to test this hypothesis. Combined the proposed aims seek to determine whether soluble A assemblies play a key role in the development of tau pathology and cognitive dysfunction.